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R. Soc. Interface."],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:p>The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) and microRNA-145-5p (miR-145) axis play a pivotal role in regulating drug resistance, apoptosis and senescence in non-small cell lung cancer (NSCLC). MALAT1 drives drug resistance by suppressing miR-145 and activating MUC1, thereby inhibiting ferroptosis; however, its precise role in regulating ferroptosis in NSCLC remains unclear. Therefore, we propose a computational modelling approach to unravel the impact of the MALAT1\/miR-145 axis on ferroptosis and drug resistance, to identify potential therapeutic strategies that promote ferroptosis. Using Boolean logic and a stochastic updating scheme, we developed and validated a robust regulatory model that encompasses ferroptosis, apoptosis, senescence and drug resistance pathways. The model, based on extensive literature and validated through gain- and loss-of-function perturbations, demonstrated strong alignment with observed clinical data that were not included in its construction. Our analysis identified three previously unreported feedback loops, miR-145\/Wip1\/p53, miR-145\/Myc\/MALAT1 and miR-145\/MUC1\/BMI1, establishing miR-145 as a central regulator in NSCLC. Perturbations targeting MALAT1 and wild-type p53-induced phosphatase 1 (Wip1) revealed potential therapeutic opportunities, with miR-145 activation emerging as a promising strategy to induce ferroptosis and overcome drug resistance. These findings highlight the MALAT1\/miR-145 axis as a transformative therapeutic target, presenting a computational foundation to advance NSCLC treatment strategies.<\/jats:p>","DOI":"10.1098\/rsif.2024.0852","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T23:08:09Z","timestamp":1748387289000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting NSCLC drug resistance: Systems biology insights into the MALAT1\/miR-145-5p axis and Wip1 in regulating ferroptosis and apoptosis"],"prefix":"10.1098","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7110-6564","authenticated-orcid":true,"given":"Shantanu","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Computer Science, University of Sao Paulo","place":["Sao Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0621-8345","authenticated-orcid":true,"given":"Daner Acunha","family":"Silveira","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Institute","place":["Porto Alegre, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6602-3905","authenticated-orcid":true,"given":"Jos\u00e9 Carlos","family":"Mombach","sequence":"additional","affiliation":[{"name":"Department of Physics, Federal University of Santa Maria","place":["Santa Maria, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-8790","authenticated-orcid":true,"given":"Ronaldo F.","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Sao Paulo","place":["Sao Paulo, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"e_1_3_8_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2020.11.019"},{"key":"e_1_3_8_3_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103961"},{"key":"e_1_3_8_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0338"},{"key":"e_1_3_8_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.01.013"},{"key":"e_1_3_8_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1595"},{"key":"e_1_3_8_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13060"},{"key":"e_1_3_8_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241713617"},{"key":"e_1_3_8_9_2","doi-asserted-by":"publisher","DOI":"10.21037\/tau-20-1526"},{"key":"e_1_3_8_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-015-1951-0"},{"key":"e_1_3_8_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808042106"},{"key":"e_1_3_8_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-00975-w"},{"key":"e_1_3_8_13_2","first-page":"4821","article-title":"Increased MALAT1 expression contributes to cisplatin resistance in non-small cell lung cancer","volume":"16","author":"Cui Y","year":"2018","unstructured":"Cui Y, Li G, Zhang X, Dai F, Zhang R. 2018 Increased MALAT1 expression contributes to cisplatin resistance in non-small cell lung cancer. 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